SUMMARY Mitochondrial and synaptic dysfunction is an early pathological feature of Alzheimer?s disease (AD) affected brain1-7. Recent studies have highlighted the role of mitochondrial A? in AD pathogenesis. A? progressively accumulates in mitochondria of AD brain and transgenic AD mice overexpressing A?. Notably, accumulation of mitochondrial A? precedes extracellular A? deposition in AD brain, which is consistent with the early onset of loss of synapses and synaptic and mitochondrial damage. Thus, accumulation of mitochondrial A? may be an initiating pathological event leading to mitochondrial and neuronal perturbation. Human PreP (hPreP) located in brain mitochondria, is a novel mitochondrial A? degrading enzyme. Our recent studies indicates that the proteolytic activity of hPreP was significantly reduced in A?-rich mitochondria from AD-affected brain and transgenic AD mice overexpressing APP/A?, suggesting that hPreP may potentially be of importance in preventing amyloid pathology of AD through its degradation and clearance of mitochondrial A?. However, the effects of PreP on amyloid pathology and mitochondrial and synaptic degeneration in A? milieu have not yet been disclosed. In our pilot studies, we observed the reduction of A? accumulation in mitochondria and cerebral cortex by increased PreP activity in Tg mAPP mice. We hypothesize that impaired function of PreP protease contributes to chronic mitochondrial A? accumulation relevant to developing amyloid pathology of AD, leading to mitochondrial and synaptic degeneration, thus, clearance of mitochondrial A? by PreP may be of importance in the pathology of AD. The goal of this proposal is to gain new insight into the role of PreP in AD pathogenesis, focusing on mitochondrial A? accumulation/clearance, amyloid pathology, synaptic mitochondrial properties, oxidative stress, synaptic function, utilizing a novel genetically manipulated transgenic mouse models and neuronal culture with altered PreP levels and proteolytic activity in A?-rich environment [(increased expression of neuronal PreP, inactive mutant PreP with catalytic base Glu(78) in the inverted zinc-binding motif replaced by Gln, lacking enzyme activity, and genetic deficiency of neuronal PreP in AD-type transgenic mice overexpressing A?). The outcomes of the project would also support that PreP might be a potential therapeutic agent for limiting mitochondrial and cerebral amyloid accumulation thereby halting AD progression.